Recent evidence indicates that human pancreatic ductal adenocarcinoma (PDA) is vulnerable to immune recognition and rejection. This raises the challenge of identifying immunotherapy strategies for PDA that are not excessively labor intensive, that consistently prolong survival, and that ideally are curative. In our effort to develop effective off-the-shelf immunotherapy against PDA, we discovered that repetitive administration of cyclophosphamide (CY) alternating with TLR agonists (TLRa) is therapeutically as or more effective than the classically synergistic combination of CY and T cell adoptive therapy. Off-the-shelf CY+TLRa treatment is much less labor intensive than adoptive therapy, is well tolerated, and is often sufficient to cure syngeneic wildtype mice of advanced PDA tumors. Remarkably, CY+TLRas therapeutic efficacy is fully abrogated by depleting host CD4+ and CD8+ T cells and NK cells, indicating that CY+TLRa successfully maintains an endogenous anti-tumor immune response even in the absence of adoptive therapy or vaccine maneuvers. An additional unique therapeutic feature is CY+TLRa's ability to convert rebounding myeloid progenitors into tumoricidal macrophages, thereby preventing tumors from differentiating them into myeloid-derived suppressor cells. Our Specific Aims are (1) to fully delineate the mechanism by which CY+TLRa treatment is therapeutically effective against mouse PDA models, to maximize translatability; (2) to perform Phase I-II clinical trials which will promptly evaluate this strategy in PDA patients, using the novel TLR8 agonist VentiRx-2337; and (3) to complete development of a vaccine strategy capable of priming T cell responses as well as reversing T cell tolerance to MUC1, which is hyperexpressed by >90% of human PDA MUC1. This will be incorporated in the CY+TLRa strategy with the goal of rendering this treatment uniformly effective for PDA.